9alpha-fluoro-delta-3, 20-diketo-11, 21-bis-oxygenated-17-hydroxy-allopregnene 3-semicarbazones and processes of preparing them



acyloXy-allopregnanes.

Unite 9a-FLUORO A 3.20 DIKETO-llJI-RIS-OXYGEN- ATED-17-HYDROXY ALLOPREGNENE 3-SEMI- CARBAZONES AND PROCESSES F PREPAR- ING THEM Richard Miller, Old Bridge, and Ralph F. Hirschmann, Scotch Plains, N.J., assi nors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey 16 Claims. (Cl. 260397.45)

This invention is concerned generally with novel steroid compounds and with processes for preparing them. More particularly, it relates to 9a-fiuoro-A -3,20-diketo- 11,21-bis-oxygenated-17-hydroxy-allopregnene compounds and to processes of preparing these compounds starting with 9a-fluoro-3,20-diketo-1l-oXygenated-17-hydroxy21- These novel 9u-fluoro-A -3,20-diketo-l1,21-bis-oxygenatcd-l7-hydroxy-allopregnene compounds possess cortisone activity, bnt differ from cortisone and hydrocortisone in not possessing any appreciable sodium or water retention action. The new compounds are especially effective in the treatment of arthritis and related diseases since they can be administered for their cortisone action without producing the undesired metabolic effects such as edema, which are caused by the sodium and water retention action of cortisone.

This application is a division of application Serial No. 511,401, filed May 26, 1955, now US. Patent No. 2,885,- 412.

These novel 9a-fiuoro-A -3,2O-diketo-11,2l-bis-oxygen- States Patent O ated-l7-hydroXy-allopregnene compounds, subject of the 7 present invention, may be chemically represented as follows:

molecule to produce the 3-semicarbazone of the corre-' sponding 9u-iuoro-A -3,20-diketo-11-oXygenated-17-hydroxy-2l-acyloxy-allopregnene compound (Compound 3). This 3-semicarbazone is then reacted with an acidic hydrolyzing agent in the presence of a carbonyl acceptor such as pyruvic acid to form the 9a-fiuoro-A -3,20-diketoll-oxygenated l7 hydroxy 21 acyloxy allopregnene (Compound 4 where R is acyl), which may be hydrolyzed, if desired, by reaction with an alcoholic solution of potassium hydroxide to produce the 9a-fiuoro-A -3,20-diketo-l1-oxygenated-17,2l-dihydroxy-allopregnene (Com- 2. pound 4 where R is hydrogen). The reactions indicated hereinabove may be chemically represented as follows:

wherein Z is a.keto or hydroxy radical, R is an'acyl radical, SC stands for a semicarbazone substituent, and R is hydrogen or an acyl radical.

The starting materials used in the foregoing process, the 9a-fluoro-3,20-diketo-l 1-oxygenated-l7-hydroxy-21 acyloxy-allopregnanes are conveniently prepared by reacting the corresponding 9a-fluoro-A -3,20-diketo-1l-oxygenated-l7-hydroXy-2l-acyloXy-pregnene (i.e. 9a-fiuorocortisone 21-acylate and 9a-fluoro-hydrocortisone 21- acylate) with hydrogen in the presence of palladium cata lyst whereby the M-unsaturated linkage is selectively reduced without substantially aflecting other reducible linkages in the molecule to produce the 9a-fluoro-3,20-diketo.- 11-oxygenated-17-hydroxy-2 l-acyloxy-allopregnane, as for example 9a-fluoro-3,l 1,20-triketo-17-hydroxy-2l-acyloxyallopregnanes such as 9u-fluoro-3,11,20-triketo-17a,21-dihydroxy-allopregnane 21-alkanoate, 9a-fiuoro-3,l1,20-triketo-l70,21-dihydroxy-allopregnane ZI-acetate, 9a-fluoro- 3,11,20-triketo 17a,21-dihydroxy-allopregnane 21-t-buty1 acetate, 9a-fluoro-3 ,1 1,20-triketo-17u,21-dihydroxy-allopregnane 2l-benzoate, 9a-fiuoro-3,11,20-diketo-11,17-di hydroxy-2l-acyloxy-allopregnanes such as 9u-fiuoro- 3,20'-diketo-l 1B,17a,21-trihydroxy-a1lopregnane -21-alkanoate, 9oc-flll0IO-3,ZO-dlkti'tO-l1fi3,17uc,21-[1lhydi'OXy-allO pregnane ZI-acetate, 9a-fi11OI0-3,20-dik6tO-11B,17oc,21-tri hydroxy-allopregnane 21-t-butylacetate', 9a-fluoro-3,20-di-lk6tO-11B,17a,21 trihydroxy allopregnane 21 benzoate, and the like.

The reaction between the t-fiUOIO-3,20-dlketO-1l-OXY- genated 17 hydroxy 21 acyloXy allopregnane and the one molecular equivalent of bromine is conveniently conducted by bringing the reactants together in an inert organic solvent as for example a halogenated hydrocarbon solvent, such as chloroform, carbon tetrachloride, a lower alkanoic acid such as acetic acid, and the'like, un-

der substantially anhydrous conditions in the presence of an acidic catalyst such as hydrogen bromide, p-tolu ene sulfonic acid, and the like. It is ordinarily preferred to treat the 9a-fluoro-3,20-diketo-1l-oxygenated 17-hydroXy-2l-acyloxy-allopregnane, in chloroform containing a catalytic amount (i.e. a few drops) of a glacial acetic acid solution of p-toluene sulfonic acid, with a solution of one molar equivalent of bromine in glacial acetic acid. The reaction is ordinarily complete in about -15 minutes. The product is conveniently recovered by evaporating the halogenated hydrocarbon solvent, such as chloroform, in vacuo, diluting the resulting mixture with water, and recovering the precipitated brominated product by filtration. This material is dissolved in dichloromethane, the resulting solution is washed with aqueous sodium bicarbonate solution and then with water, and dried. The dried dichloromethane solution is evaporated to dryness, and the residual material is recrystallized from acetonitrile to give the 2-br0mo-9o1- fluoro 3,20 diketo 11 oxygenated 17 hydroxy- 2l-acyloxy-allopregnane, as for example 2-bromo-9afluoro 3,11,20 triketo 17. hydroxy 2'1 acyloxyallopregnanes such as 2-bromo-9a-fluoro-3,l1,20-triketo- 1701,21 dihydroxy allopregnane 21 acetate, 2 bromo- 91x fluoro 3,11,20 triketo 1702,21 dihydroxy allopregnane 2l-t-butylacetate or other 2-bromo-9a-fluoro- 3,11,20 triketo 1701,21 dihydroxy allopregnane 21- alkanoate, 2 bromo 9oz fluoro- 3,20 diketo 115, 17a dihydroxy 21 acyloxy allopregnanes such as 2 bromo 9111 fluoro 3,20 diketo 111531711121 trihydroxy-allopregnane 2l-alkanoate, 2-bromo-9e1-fiuoro- 3,20 diketo l1'/8,171z,21 trihydroxy allopregnane 21- acetate, 2-bromo-9e-fiuoro-3,20diketo-l 1B,17111,21-trihydroxy-allopregnane 21-t-butylacetate, 2-bromo-9'o1-fluoro- 3,20 diketo 11B,17a,21 trihydroxy allopregnane 21-benzoate, and the like.

The reaction between the 2-bromo-9u-fiuo'ro-3,20-diketo 11 oxygenated 17 hydroxy 21 acyloxyallopregnane compound and semicarbazide is ordinarily conducted by bringing the reactants together in the presence of an organic solvent, preferably acetonitrile, a chlorinated hydrocarbon, such as chloroform, and the like. The semicarbazide is conveniently prepared in the reaction mixture by treating a salt of semicarbazide, such as semicarbazide hydrochloride, with a basic substance such as sodium acetate. It is. preferred to. treat the 2 bromo 9111 fluoro 3,20 diketo 11 oxygenated 17- hydroxy-21-acyloxyallopregnane compound in acetonitrile solution with an aqueous solution of'semicarbazide hydrochloride and sodium acetate under. an inert atmosphere. such as nitrogen, at approximately room temper ature, under which conditions the reaction is usually com plete in about 4-5 hours. The material whichprecipitates fromthe reaction solution is recovered. by filtration, and washed with water to give the 3-semicarbazone of the 91:1-fiuoro-A -3,ZO-diketo-l1-oxygenated-17-hydroxy- 21-acyloxy-allopregnene compound as for example a 9n:- fluoro A 3,11,20 triketo 1701 hydroxy 21 acyloxy-allopregnene 3-semicarbazone such as a 91x-fluoro-A 3,11,20 triketo 1701,21 dihydroxy allopregnene 3- semicarbazone 2l-alkanoate, 9111-fiuoro-A -3,11,20-triketo- 1701,21 dihydroxy allopregnene 3 semicarbazone 21- acetate, 901 fluoro A 3,11,20 triketo 1701,21 dihydroxy-allopregnene 3-semicarbazone 21-t-butylacetate, 912 fluoro A 3,11,20 triketo 1701,21 dihydroxyallopregnene 3-semicarbazone 21-benzoate, a 9a-fluoro- A 3,20 diketo 1119,1701 dihydroxy 21 acyloxyallopregnene 3-semicarbazone, such as 91 1-fluoro-A -3,20- diketo 11;8,17o1,21 trihydroxy allopregnene 3 semicarbazone 21-alkanoate, 9a-fluoro-A -3,2O-diketo-11,8,17111, 2-1-trihydroxy-allopregnene 3-semicarbazone 21-acetate, 91xfiuoro A 3,20 diketo llfl,l7a,21 trihydroxyallopregnene 3-semicarbazone 2l-t-butylacetate, 9zx-fill0- ro A 3,20 diketo 11fi,17oc,21 trihydroxy allopregnene 3-semicarbazone 21-benzoate, and the like.

- The hydrolysis of this 3-semicarbazone is convenient- 1y: conducted by bringing the 91:1-fiuoro-A -3,20-diketo- 11.- oxygenated 17 hydroxy 21 acyloxy allopregnene 3-semicarbazone compound into intimate contact with an aqueous solution of an acid as for example an organic acid such as acetic acid. propionic acid, a mineral acid such as sulphuric acid, hydrohalic acid, hydro.-

chloric acid, phosphoric acid, and the like, preferably in the presence of a carbonyl acceptor such as pyruvic acid, and maintaining the resulting mixture at a temperature from about room temperature to about 100 C. Under these conditions the hydrolysis reaction is ordinarily com: plete in about 30 minute at the more elevated tempera ture, and in'about' 24 hours when the reaction is conducted at room temperature. In accordance with this preferred hydrolysis procedure utilizing aqueous acetic acid and pyruvic acid, there is obtained the corresponding 9a fluoro A 3,20 diketo 11 oxygenated 17- hydroxy 21 acyloxy allopregnene compound as for example 9111 fluoro A 3,11,20 triketo 1701 hydroxy-2l-acyloxy-allopregnenes such as 9111-fiuoro-A -3,11, 20 triketo 1701,21 dihydroxy allopregnene 21 alkanoate, 91: fluoro A 3,11,20 triketo 1711,21 dihydroxy-allopregnene 21-acetate, 9a-fiuoro-A -3,11,20- triketo 1711,2l dihydroxy allopregnene 21 t butylacetate, fluoro -A 3,11,20 triketo 1701,21 dihydroxy-allopregnene' 2'1-benzoate', 9a-fiuoro-A -3,20-diketo 1113,1711: dihydroxy 21 acyloxy allopregnenes such as. 9a-fluoro-A -3,20-dilreto-11;3,171x,21-trihydroxy* allopregnene 21-alkanoate, 91:1-fluoro-A -3,2O-diketo-11 8, 1711,21 trihydroxy allopregnene 21 acetate, 901 fluoro A 3,20 diketo 11B,l7a,21 trihydroxy allopregnene 21 t butylacetate, 9a fluoro A 3,20 di keto 11fi,l7a,21 trihydroxy allopregnene 21 benzoate, and the like. The 9a-fluoro-A -3,11,20-triketo-l7ahydroxy-2l-acyloxy-allopregnene and the 91'11-fluo'ro-A -3, 20 diketo 11,8,17111 dihydroxy 21 acyloxy allopregnene may be hydrolyzed, if desired, by reaction with an alcoholic solution of potassium hydroxide to produce 91:: fluoro A 3,11,20 triketo 1711,21 dihydroxy allopregnene and 9a fluoro A 3,20 diketo 11B, 17a,21-trihydroxy-allopregnene, respectively.

The following examples illustrate methods of carrying out the present invention but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 Four grams of 9ocfitl0IO-3,20diket0-11B,17oc,21-t1l hydroxy-allopregnane 21-acetate is dissolved in 200 cc. of chloroform, a few drops of an acetic acid solution of p-toluene sulfonic acid monohydrate is added to the solution, and to the resulting solution is added an acetic acid solution of bromine containing one molar equivalent of bromine. The resultingmixture is stirred for a few minutes to complete decolorization of the bromine, the chloroform is evaporated from the reaction mixture in vacuo, and the acetic acid reaction mixture is mixed with water and ice thereby precipitating the brominated steroid product. This precipitated material is recovered by filtration to give crude 2-bromo-9o1-fluoro-3,20-diketol1t ,1711,21-trihydroxy-allopregnane 21-acetate. The latter material is dissolved in dichloromethane, and the resulting solution is washed with an aqueous sodium bicarbonate solution and then with Water, and dried over anhydrous magnesium sulfate. The dried solution is evaporated to dryness in vacuo, and the residual material recrystallized from acetonitrile to give substantially pure 2 bromo 9a fluoro 3,20 diketo 1lB,17a,21 trihydroxy-allopregnane 21-acetate.

The 2 bromo 9a fluoro 3,20 diketo 11 3,1701, 2l-trihydroxy-allopregnane 21-acetate is dissolved in acetonitrile and the resulting solution is mixed with an aqueous solution of semicarbazide hydrochloride and sodium acetate. The resulting mixture is maintained under an inert (nitrogen) atmosphere for a period of about 4 /2 hours, and the precipitated material is recovered by filtration and washed with water to give 911- fluoro A 3,20 diketo l1{3,17a,21 trihydroxy allopregnene 3-semicarbazone 21-acetate.

Example 2 About 0.620 g. of 9a-fluoro-A -3,20-diketo-115,1711, 21trihydroxy-allopregnene 3-semicarbazone 21-acetate is suspended in 18.2 cc. of glacial acetic acid and 7.3 cc. of Water, about 0.19 cc. of pyruvic acid is added, and the resulting mixture is allowed to stand in contact with an inert (nitrogen) atmosphere for a period of about 20 hours at room temperature. The resulting mixture is diluted with chloroform, the chloroform mixture is washed repeatedly with water, and the solvents are evaporated from the chloroform solution. The residual material is chro-matographed over neutral alumina to give substantially pure 9ot-fiuoro-A -3,20-diketo-l1fi,l7a,2ltrihydroxy-allopregnene 2l-acetate; M.P. approximately 237 C.; [al +34.9 in acetone; u.v. )tmax in methanol 222 m (log E 4.03);

2.98 IL, 5.73 n, 5.78 ,u, 6.05 The 9a-fluoro-A -3,20- diketo-1113,170:,2ltrihydroxy-allopregnene 2l-acetate may be hydrolyzed by treatment with potassium hydroxide in methanol at room temperature to give 9a-fiuoro-A 3,20-diketo-1 1 3,17)1trihydroxy-alloprcgnene.

Example 3 In accordance with the procedure set forth in Example 1 hereinabove, and utilizing as starting material 9oz fluoro 3,11,20 triketo 17a,2l dihydroxy allopregnane 21-acetate in place of the 9a-fluoro-3,20- diketo-1113,l7a,2l-al1opregnane 21-acetate used in Example 1, there are obtained 2-bromo-9a-fiuoro-3J1,20- triketo-17a,21dihydroxy-allopregnane ZI-acetate and 9afluoro A 3,11,20 triketo 1711,21 dihydroxy allopregnene 3-semicarbazone 2l-acctate.

In accordance with the procedure set forth in Example 2 hereinabove, and utilizing as starting material 90: fluoro A 3,11.20 triketo 1711,21 dihydroxy allopregnene 3-semicarbazone 2l-acetate, there are obtained 9a fluoro A 3,11,20 triketo 17a,2l dihydroxy-allopregnene 21-acetate and 9a-fil1O1'O-A -3,11,20- triketo-1711,21-dihydroxy-allopregnene.

The 9a fluoro 3,20 diketo 11,6,17u,21 trihydroxy-allopregnane 2l-acetate, utilized as starting material in Example 1 hereinabove, may be prepared starting with 9a-fluoro-hydrocortisone acetate (A -9a-fluoro 3,20 diketo 11,8,17a,21 trihydroxy pregnene 21 acetate) as follows: 6.0 g. of 5% palladium on charcoal catalyst are added to a suspension of 7.25 g. of said A 9a fiuoro 3,20 diketo 11,3,l7a,21 trihydroxy pregnene ZI-acetate in 750 cc. of methanol, and the mixture is reacted with hydrogen at atmospheric pres sure while maintaining the reactants at about room temperature. The absorption of hydrogen ceases after about 15 minutes; the amount of hydrogen absorbed corresponds to one mole. The reaction mixture is filtered, thereby removing the catalyst, and the catalyst is washed thoroughly with methanol. The filtrate and washings are combined, and the resulting solution is evaporated to dryness in vacuo. The residual material is then recrystallized twice from acetone to give about 4 grams of substantially pure 90c fluoro 3,20 diketo 115,17a dihydroxy-al-acetoxy-allopregnane.

The 9 fluoro 2,1 1,20 triketo 17a,21 dihydroxy allopregnane 21-acetate, utilized as starting material in Example 3 hereinabove, may be prepared by hydrogenating 9a-fiuoro-cortisone acetate (A -9a-fiuoro-3,1l, 20-triketo-l7u,2l-dihydroxy-pregnene 21-acetate) in accordance with the foregoing hydrogenation procedure using 5% palladium on charcoal as the hydrogenation catalyst.

Various changes and modifications may be made in carrying out the present invention Without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. The process which comprises reacting 9ot-fluoro- 3,11,20-triketo-17ot-hydroxy 21 lower alkanoyloxy-allopregnane with one molecular equivalent of bromine to form the corresponding 2-bromo-9a-fluoro-3,l1,20-triketo- 170c-hYdI'OXY-2l-1OW6I alkanoyloxy-allopregnane.

2. The process which comprises reacting 9a-fluor0- 3,11,20 triketo 17a,2l dihydroxy-allopregnane 21- acetate with bromine in chloroform and acetic acid, in the presence of p-toluene sulfonic acid catalyst, thereby forming 9a-fluoro-2-brorno-3,11,20-triketo-17a-hydroxy- 21acetoxy-allopregnane.

3. The process which comprises reacting 9oc-fl11010- 3,20-diketo-l1,8,17ot-dihydroxy-2l-lower alkanoyloxy-allopregnane with one molecular equivalent of bromine to form the corresponding 2-bromo-9ot-fluoro-3,20-diketo- 1 1,3,l7oc-dihYdI0XY-21-10W61 alkanoyloxy-allopregnane.

4. The process which comprises reacting 9u-fluoro- 3,20 diketo-11,6,17a-dihydroxy-21acetoxy-allopregnane with bromine in chloroform and acetic acid in the presence of p-toluene sulfonic acid catalyst, thereby forming 2- bromo 9a fluoro 3,20 diketo-llfi,17x-dihydroxy-21- acetoxy-allopregnane.

5. The process which comprises reacting 2-bromo-9afluoro-3,11,20-triketo-17a-hydroxy-21-lower alkanoyloxy-- allopregnane with semicarbazide to produce 9O6-flllOIO-A 3,11,20-triketo-17u-hydroxy 2l-lower alkanoyloxy-allopregnene 3-semicarbazone.

6. The process which comprises reacting 2-bromo-9mfluoro-3,11,20 triketo 17a,2l dihydroxy-allopregnane- 2l-acetate with semicarbazide to produce 9ct-fluoro-A -3, 11,20-triketo-l7ot,21 dihydroxy-allopregnene 3-sernicarbazone 21-acetate.

7. The process which comprises reacting Z-bIOmO-9afluoro-3,20-diketo-1 1 B, 170L-d1hYClI'OXY-2l-1OWI alkanoyloxy-allopregnane with semicarbazide to produce 9afluoro A 3,20-diketo-1 1 {3,17ot-dihydroxy-21-lower alkanoyloxy-allopregnene 3-semicarbazone.

8. The process which comprises reacting 2-bromo-9afluoro 3,20 diketo 11fi,17ot,21 trihydroxy-allopregnane 21-acetate with semicarbazide to produce 9a-fluoro- A -3,20-diketo-11B,17a,21trihydroxy-allopregnene 3-semicarbazone 21-acetate.

9. 9a fluoro A 3,11,20 triketo-l7u,21-dihydroxyallopregnene 3-semicarbazone 2l-lower alkanoate.

10. 9a fluoro A 3,11,20 triketo-17a,21-dihydroxyallopregnene 3-semicarbazone 2l-acetate.

l1. t-flllO1'O A 3,20 diketo 11/3,17a,21 trihydroxy-allopregnene 3-semicarbazone 21-loWer alkanoate.

12. 90c fluoro A 3,20 diketo 11fi,17a,21 trihydroxy-allopregnene 3-semicarbazone 21-acetate.

13. 2 bromo 90c fluoro 3,11,20 triketo :,21- dihydroxy-allopregnane 2l-lower alkanoate.

l4. 2 bromo 9a fluoro 3,11,20 triketo 1704,21- dihydroxy-allopregnane 21-acetate.

15. 2 bromo 90c fluoro 3,20 diketo 1113,17a,21- trihydroxy-allopregnane 21-lower alkanoate.

16. 2 bromo 9a fluoro 3,20 diketo 11fl,17oc,21- trihydroxy-allopregnane 21-acetate.

Krsek Jan. 24, 1956 Sarett Feb. 28, 1956 

9. 9A - FLUORO - $1 - 3,11,20 - TRIKETO-17A,21-DIHYDROXYALLOPREGNENE 3-SEMICARBAZONE 21-LOWER ALKANOATE.
 13. 2 - BROMO - 9A - FLUORO - 3,11,20 - TRIKETO - 17A,21DIHYDROXY-ALLOPREGNANE 21-LOWER ALKANOATE. 